The overall thrust of this program is directed towards a better understanding of the factors, cellular and humoral, which regulate normal hematopoiesis in animals and man, which will then function as a probe into the abnormalities in these systems responsible for bone marrow failure. We will investigate the role of cellular elements and their humoral products which regulate the self replication, proliferation, and maturation of hematopoietic progenitor cells. Utilizing murine models including the W/Wv and S1/S1d anemic mouse models, congeneic mouse strains, and normal mice as sources of bone marrow and peripheral blood cells, we will attempt to identify and characterize specific subpopulations of cells responsible for the regulation of hematopoietic cell proliferation. We will also evaluate the appearance of these subpopulations in ontogeny. The specific subpopulations identified will then be further evaluated utilizing co-culture techniques and conditioned media production in order to determine their mechanism of action (soluble factors versus direct cell-cell interactions). We will evaluate the role of such regulatory cells and soluble factors in in vitro clonal assay systems (CFU-c, BFU-e and CFU-e) as well as in diffusion chamber assays and long term continuous bone marrow cultures. Similar studies will be carried out (with normal and perturbed) human bone marrow and peripheral blood as well. These will be done with cell populations from the peripheral blood and bone marrow of normal human volunteers and patients with bone marrow failure both before and during their recovery following bone marrow transplantation.